tbuckley/cabot-search huggingface dataset:
Abstract IA025: Decoding breast cancer evolution with single cell genomics
Authors: Nicholas Navin
Journal: Cancer Research (2022)

Abstract I will discuss our efforts to develop and apply single cell DNA sequencing technologies to study breast cancer progression and evolution. We have developed a method called Acoustic Cell Tagmentation (ACT) which can provide high-throughput single cell copy number profiling of hundreds of cells in parallel at single-molecule resolution. We have applied this approach to study copy number evolution in Triple-negative breast cancer, which has revealed a ‘transient instability’ model of early copy number evolution, after the acquisition of TP53 mutations and genome doubling. We have also developed a computational toolkit called CopyKit to analyze single cell DNA sequencing data, and applied it to study metastasis in breast and colon cancer, as well as the spatial organization of subclones in metastatic tumors. Collectively these studies and tools provide new insights into the evolution of chromosome aberrations in human tumors. Citation Format: Nicholas Navin. Decoding breast cancer evolution with single cell genomics [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA025.
Critical involvement of lysyl oxidase in seizure-induced neuronal damage through ERK-Alox5-dependent ferroptosis and its therapeutic implications
Authors: Xiaoyuan Mao, Xuan Wang, Mingzhu Jin, Qin Li, Jining Jia, Menghuan Li, Honghao Zhou, Zhaoqian Liu, Weilin Jin, Yanli Zhao, Zhong Luo
Journal: Acta Pharmaceutica Sinica B (2022)

Recent insights collectively suggest the important roles of lysyl oxidase (LysOX) in the pathological processes of several acute and chronic neurological diseases, but the molecular regulatory mechanisms remain elusive. Herein, we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of neurons. Mechanistically, LysOX promotes ferroptosis-associated lipid peroxidation in neurons via activating extracellular regulated protein kinase (ERK)-dependent 5-lipoxygenase (Alox5) signaling. In addition, overexpression of LysOX via adeno-associated viral vector (AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage. Our studies show that pharmacological inhibition of LysOX with β-aminopropionitrile (BAPN) significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage, while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based nanocarriers. These findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal damage. Suppressing this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury.
Apoptotic extracellular vesicles are metabolized regulators nurturing the skin and hair
Authors: Lan Ma, Chider Chen, Dawei Liu, Zhiqing Huang, Jiaqi Li, Haixiang Liu, Ryan Tsz Kin Kwok, Benzhong Tang, Bingdong Sui, Xiao Zhang, Jianxia Tang, Xueli Mao, Weiying Huang, Songtao Shi, Xiaoxing Kou
Journal: Bioactive Materials (2022)

Over 300 billion of cells die every day in the human body, producing a large number of endogenous apoptotic extracellular vesicles (apoEVs). Also, allogenic stem cell transplantation, a commonly used therapeutic approach in current clinical practice, generates exogenous apoEVs. It is well known that phagocytic cells engulf and digest apoEVs to maintain the body's homeostasis. In this study, we show that a fraction of exogenous apoEVs is metabolized in the integumentary skin and hair follicles. Mechanistically, apoEVs activate the Wnt/β-catenin pathway to facilitate their metabolism in a wave-like pattern. The migration of apoEVs is enhanced by treadmill exercise and inhibited by tail suspension, which is associated with the mechanical force-regulated expression of DKK1 in circulation. Furthermore, we show that exogenous apoEVs promote wound healing and hair growth via activation of Wnt/β-catenin pathway in skin and hair follicle mesenchymal stem cells. This study reveals a previously unrecognized metabolic pathway of apoEVs and opens a new avenue for exploring apoEV-based therapy for skin and hair disorders.
Genetics, pathobiology and therapeutic opportunities of polycystic liver disease
Authors: Paula Olaizola, Pedro M. Rodrigues, Francisco J. Caballero-Camino, Laura Izquierdo-Sanchez, Patricia Aspichueta, Luis Bujanda, Nicholas F. Larusso, Joost P. H. Drenth, Maria J. Perugorria, Jesus M. Banales
Journal: Nature Reviews Gastroenterology & Hepatology (2022)
Diagnostic and Prognostic Value of Myocardial Work Indices for Identification of Cancer Therapy–Related Cardiotoxicity
Authors: Oscar Calvillo-Argüelles, Babitha Thampinathan, Emily Somerset, Tamar Shalmon, Eitan Amir, Chun-Po Steve Fan, Sangkyu Moon, Husam Abdel-Qadir, Yobiga Thevakumaran, Jennifer Day, Anna Woo, Bernd J Wintersperger, Thomas H Marwick, Paaladinesh Thavendiranathan
Journal: JACC. Cardiovascular imaging (2022)
Combining immune checkpoint blockade with ATP-based immunogenic cell death amplifier for cancer chemo-immunotherapy
Authors: Jiulong Zhang, Xiaoyan Sun, Xiufeng Zhao, Chunrong Yang, Menghao Shi, Benzhuo Zhang, Haiyang Hu, Mingxi Qiao, Dawei Chen, Xiuli Zhao
Journal: Acta Pharmaceutica Sinica B (2022)

Amplifying "eat me signal" during tumor immunogenic cell death (ICD) cascade is crucial for tumor immunotherapy. Inspired by the indispensable role of adenosine triphosphate (ATP, a necessary "eat me signal" for ICD), a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy. Doxorubicin (DOX), ATP and ferrous ions (Fe2+) were co-assembled into nanosized amplifier (ADO-Fe) through π‒π stacking and coordination effect. Meanwhile, phenylboric acid-polyethylene glycol-phenylboric acid (PBA-PEG-PBA) was modified on the surface of ADO-Fe (denoted as PADO-Fe) by the virtue of d-ribose unit of ATP. PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction. In acidic microenvironment, PBA-PEG-PBA would dissociate from amplifier. Moreover, high H2O2 concentration would induce hydroxyl radical (·OH) and oxygen (O2) generation through Fenton reaction by Fe2+. DOX and ATP would be released from the amplifier, which could induce ICD effect and "ICD adjuvant" to amplify this process. Together with programmed death ligands 1 (PD-L1) checkpoint blockade immunotherapy, PADO-Fe could not only activate immune response against primary tumor, but also strong abscopal effect against distant tumor. Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.
Nano-calcium silicate mineralized fish scale scaffolds for enhancing tendon-bone healing
Authors: Fei Han, Tian Li, Mengmeng Li, Bingjun Zhang, Yufeng Wang, Yufang Zhu, Chengtie Wu
Journal: Bioactive Materials (2022)

Tendon-bone healing is essential for an effective rotator cuff tendon repair surgery, however, this remains a significant challenge due to the lack of biomaterials with high strength and bioactivity. Inspired by the high-performance exoskeleton of natural organisms, we set out to apply natural fish scale (FS) modified by calcium silicate nanoparticles (CS NPs) as a new biomaterial (CS-FS) to overcome the challenge. Benefit from its "Bouligand" microstructure, such FS-based scaffold maintained excellent tensile strength (125.05 MPa) and toughness (14.16 MJ/m3), which are 1.93 and 2.72 times that of natural tendon respectively, allowing it to well meet the requirements for rotator cuff tendon repair. Additionally, CS-FS showed diverse bioactivities by stimulating the differentiation and phenotypic maintenance of multiple types of cells participated into the composition of tendon-bone junction, (e.g. bone marrow mesenchymal stem cells (BMSCs), chondrocyte, and tendon stem/progenitor cells (TSPCs)). In both rat and rabbit rotator cuff tear (RCT) models, CS-FS played a key role in the tendon-bone interface regeneration and biomechanical function, which may be achieved by activating BMP-2/Smad/Runx2 pathway in BMSCs. Therefore, natural fish scale -based biomaterials are the promising candidate for clinical tendon repair due to their outstanding strength and bioactivity.
Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages’ transition into a pro-inflammatory state
Authors: Laura A Bosmans, Claudia M van Tiel, Suzanne A B M Aarts, Lisa Willemsen, Jeroen Baardman, Bram W van Os, Myrthe den Toom, Linda Beckers, David J Ahern, Johannes H M Levels, Aldo Jongejan, Perry D Moerland, Sanne G S Verberk, Jan van den Bossche, Menno M P J de Winther, Christian Weber, Dorothee Atzler, Claudia Monaco, Norbert Gerdes, Annelie Shami, Esther Lutgens
Journal: Cardiovascular Research (2022)

Abstract Aims CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. Method and Results Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe−/− background were generated (CD40wt and CD40mac−/−, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac−/− compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac−/− atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b− macrophages in the atherosclerotic aorta of CD40mac−/− compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac−/− mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1). Conclusions We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.
Strong, steady and straight: UK consensus statement on physical activity and exercise for osteoporosis
Authors: Katherine Brooke-Wavell, Dawn A Skelton, Karen L Barker, Emma M Clark, Sarah De Biase, Susanne Arnold, Zoe Paskins, Katie R Robinson, Rachel M Lewis, Jonathan H Tobias, Kate A Ward, Julie Whitney, Sarah Leyland
Journal: British Journal of Sports Medicine (2022)

Exercise and physical activity can improve bone strength and the risk of falls, which may offer benefits in the prevention and management of osteoporosis. However, uncertainty about the types of exercise that are safe and effective instigates lack of confidence in people with osteoporosis and health professionals. Existing guidelines leave some questions unresolved. This consensus statement aimed to determine the physical activity and exercise needed to optimise bone strength, reduce fall and fracture risk, improve posture and manage vertebral fracture symptoms, while minimising potential risks in people with osteoporosis. The scope of this statement was developed following stakeholder consultation. Meta-analyses were reviewed and where evidence was lacking, individual studies or expert opinion were used to develop recommendations. A multidisciplinary expert group reviewed evidence to make recommendations, by consensus when evidence was not available. Key recommendations are that people with osteoporosis should undertake (1) resistance and impact exercise to maximise bone strength; (2) activities to improve strength and balance to reduce falls; (3) spinal extension exercise to improve posture and potentially reduce risk of falls and vertebral fractures. For safety, we recommend avoiding postures involving a high degree of spinal flexion during exercise or daily life. People with vertebral fracture or multiple low trauma fractures should usually exercise only up to an impact equivalent to brisk walking. Those at risk of falls should start with targeted strength and balance training. Vertebral fracture symptoms may benefit from exercise to reduce pain, improve mobility and quality of life, ideally with specialist advice to encourage return to normal activities. Everyone with osteoporosis may benefit from guidance on adapting postures and movements. There is little evidence that physical activity is associated with significant harm, and the benefits, in general, outweigh the risks.
Abstract B038: Blockade of c-met signaling to circumvent radioresistance-associated metastasis in head and neck cancer
Authors: Juan Dou, Liwei Lang, Georgia Chen, Nabil F. Saba, Yong Teng
Journal: Cancer Research (2022)

Abstract One of the significant clinical challenges in head and neck cancer (HNC) treatment is a high rate of recurrence and metastasis after radiotherapy. Once tumor metastasis occurs following radiotherapy, the prognosis of HNC patients is extremely poor. However, the failure of radiotherapy for cancers is closely related to various factors, and the underlying mechanism remains unclear. We report here that c-Met is the most activated receptor tyrosine kinases in HNC cells once they develop radioresistance. Inactivation of c-Met dramatically attenuates the increased metastatic potential gained in HNC radioresistant cells, leading to tumor regression. Cancer stem cells (CSC) have been confirmed to be in a quiescent state in most established tumors. Mechanistically, the quiescent CSC population can be “awakened” by hyperactive c-Met signaling in radiation, which in turn initiates proliferation and differentiation to potentiate a series of malignant phenotypes. Most importantly, knockdown c-Met by shRNAs or inactivating it by c-Met inhibitor SU11274 reduces the population of “awakened” CSCs and suppresses metastasis, leading to increased sensitivity of HNC radioresistant cells to radiation. These novel findings highlight the importance of additional c-Met blockade in radiotherapy and suggest that combined targeting of c-Met and radiotherapy could be a promising strategy to improve the care for patients with HNC. Citation Format: Juan Dou, Liwei Lang, Georgia Chen, Nabil F. Saba, Yong Teng. Blockade of c-met signaling to circumvent radioresistance-associated metastasis in head and neck cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B038.
Too much water drowned the miller: Akkermansia determines immunotherapy responses
Authors: Le Li, Florencia McAllister
Journal: Cell Reports Medicine (2022)

Derosa et al.1 demonstrated that intestinal Akkermansia muciniphila predicts vigorous response to immunotherapy in non-small-cell lung cancer. Baseline level of this microbe has better value than PD-L1 expression and represents a unique approach for stratifying patients that can benefit from immunotherapy.
Rifapentine access in Europe: growing concerns over key tuberculosis treatment component
Authors: Lorenzo Guglielmetti, Gunar Günther, Claude Leu, Daniela Cirillo, Raquel Duarte, Alberto L. Garcia-Basteiro, Delia Goletti, Mateja Jankovic, Liga Kuksa, Florian P. Maurer, Frédéric Méchaï, Simon Tiberi, Frank van Leth, Nicolas Veziris, Christoph Lange
Journal: European Respiratory Journal (2022)

Robert Bridges OM is the only medical graduate (he was elected to the Fellowship of the Royal College of Physicians of London in 1900) to have held the office of Poet Laureate. Educated at Corpus Christi College, Oxford and St Bartholomew's Hospital he practised as a casualty physician at his teaching hospital (where he made a series of highly critical remarks of the Victorian medical establishment) and subsequently as a full physician to the Great (later Royal) Northern Hospital. He was also a physician to the Hospital for Sick Children. It had for long been his intention to retire from the medical profession at the early age of 40! In 1913, Bridges was appointed Poet Laureate by King George V, and following a disappointingly sparse output of "official" work, published his greatest literary contribution—<i>The Testament of Beauty</i>—on his 85th birthday.
Hydroxycholesterol substitution in ionizable lipid nanoparticles for mRNA delivery to T cells
Authors: Savan K. Patel, Margaret M. Billingsley, Caitlin Frazee, Xuexiang Han, Kelsey L. Swingle, Jingya Qin, Mohamad-Gabriel Alameh, Karin Wang, Drew Weissman, Michael J. Mitchell
Journal: Journal of Controlled Release (2022)
Coronary Atherosclerosis in an Asymptomatic U.S. Population
Authors: Khurram Nasir, Miguel Cainzos-Achirica, Javier Valero-Elizondo, Shozab S. Ali, Ruby Havistin, Suvasini Lakshman, Michael J. Blaha, Ron Blankstein, Michael D. Shapiro, Lara Arias, Anshul Saxena, Theodore Feldman, Matthew J. Budoff, Jack A. Ziffer, Jonathan Fialkow, Ricardo C. Cury
Journal: JACC. Cardiovascular imaging (2022)
Abstract PR013: Oct4 and Sox2 induce cellular transition of glioma stem cells to an immune suppressive, regulatory T cell-like state
Authors: Amanda Johnson, Jack Korleski, John Laterra, Hernando Lopez-Bertoni
Journal: Cancer Research (2022)

Abstract Solid malignancies, including GBM, contain small subsets of cells that display stem-like properties (i.e. glioma stem cells or GSCs) and act as key determinants of therapeutic resistance and tumor recurrence. Mechanisms of GSC immune escape are considered fundamental to clinical GBM growth and recurrence. GBM cells escape antitumor immunity by modifying the tumor microenvironment by secreting immune-suppressive factors and recruiting anti-inflammatory/pro-oncogenic cells (e.g. T-regulatory cells, M2-like macrophages). However, whether subsets of GSCs can mimic T-reg-like functions by expressing proteins associated with T-reg immune-suppression remains unknown. Single-cell RNA sequencing analysis of GBM neurospheres revealed a previously unrecognized Oct4/Sox2high/FOXP3− cell subpopulation with high expression of TGFb1, CD39, CD73, PD-L1, and Galectin-1, a gene expression fingerprint typically associated with T-reg cells and their immune suppressive functions within the tumor microenvironment. Bioinformatics analysis of public databases shows that the above-mentioned genes are enriched in the mesenchymal GBM subtype and highly correlated with CD44 and TGFb type II receptor (TGFBR2) expression in both clinical GBM and primary GSCs. Mechanistically, Oct4 and Sox2 were found to directly induce TGFBR2 transcription concurrent with chromatin architectural changes (i.e. heterochromatin-to-euchromatin transition) involving the TGFBR2 gene. Transgenic TGFBR2 expression increased neurosphere cell growth capacity, upregulated expression of T-reg-like effector genes and enriched for CD44+ GSCs. Functionally, neurospheres expressing transgenic Oct4/Sox2 or transgenic TGFBR2 possess increased immunosuppressive capacity, and pharmacological inhibition of TGFBR2 depleted CD44+ GSCs and reduced immunosuppression in T-cell co-cultures. Taken together, we show that reprogramming events initiated by Oct4 and Sox2 induce a CD44+/FOX3P− GSC cell subset with a T-reg-like immunosuppressive transcriptional profile via a TGFBR2-dependent mechanism. This research provides the first description of such neoplastic cells in any malignancy and has high potential translational impact since targeting these tumor cell subsets and their immunosuppressive mechanisms may be critical to the successful development of GBM immunotherapies. Citation Format: Amanda Johnson, Jack Korleski, John Laterra, Hernando Lopez-Bertoni. Oct4 and Sox2 induce cellular transition of glioma stem cells to an immune suppressive, regulatory T cell-like state [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR013.
<scp>Nontypeable <i>Haemophilus influenzae</i></scp> infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma
Authors: Jodie Ackland, Clair Barber, Ashley Heinson, Adnan Azim, David W. Cleary, Myron Christodoulides, Ramesh J. Kurukulaaratchy, Peter Howarth, Tom M. A. Wilkinson, Karl J. Staples
Journal: Allergy (2022)

Abstract Background Nontypeable Haemophilus influenzae (NTHi) is a respiratory tract pathobiont that chronically colonizes the airways of asthma patients and is associated with severe, neutrophilic disease phenotypes. The mechanism of NTHi airway persistence is not well understood, but accumulating evidence suggests NTHi can persist within host airway immune cells such as macrophages. We hypothesized that NTHi infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma. Methods Bronchoalveolar lavage (BAL) samples from 25 severe asthma patients were assessed by fluorescence in situ hybridisation to quantify NTHi presence. Weighted gene correlation network analysis (WGCNA) was performed on RNASeq data from NTHi‐infected monocyte‐derived macrophages to identify transcriptomic networks associated with NTHi infection. Results NTHi was detected in 56% of BAL samples (NTHi+) and was associated with longer asthma duration (34 vs 22.5 years, p = .0436) and higher sputum neutrophil proportion (67% vs 25%, p = .0462). WGCNA identified a transcriptomic network of immune‐related macrophage genes significantly associated with NTHi infection, including upregulation of T17 inflammatory mediators and neutrophil chemoattractants IL1B, IL8, IL23 and CCL20 (all p &lt; .05). Macrophage network genes SGPP2 ( p = .0221), IL1B ( p = .0014) and GBP1 ( p = .0477) were more highly expressed in NTHi+ BAL and moderately correlated with asthma duration ( IL1B ; rho = 0.41, p = .041) and lower prebronchodilator FEV1/FVC% ( GBP1 ; rho = −0.43, p = .046 and IL1B ; rho = −0.42, p = .055). Conclusions NTHi persistence with pulmonary macrophages may contribute to chronic airway inflammation and T17 responses in severe asthma, which can lead to decreased lung function and reduced steroid responsiveness. Identifying therapeutic strategies to reduce the burden of NTHi in asthma could improve patient outcomes.
Evolving Role of Calcium Density in Coronary Artery Calcium Scoring and Atherosclerotic Cardiovascular Disease Risk
Authors: Alexander C. Razavi, Arthur S. Agatston, Leslee J. Shaw, Carlo N. De Cecco, Marly van Assen, Laurence S. Sperling, Marcio S. Bittencourt, Melissa A. Daubert, Khurram Nasir, Roger S. Blumenthal, Martin Bødtker Mortensen, Seamus P. Whelton, Michael J. Blaha, Omar Dzaye
Journal: JACC. Cardiovascular imaging (2022)